Mueller E, Sarraf P, Tontonoz P, Evans R M, Martin K J, Zhang M, Fletcher C, Singer S, Spiegelman B M
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mol Cell. 1998 Feb;1(3):465-70. doi: 10.1016/s1097-2765(00)80047-7.
We have previously demonstrated that PPAR gamma stimulates the terminal differentiation of adipocyte precursors when activated by synthetic ligands, such as the antidiabetic thiazolidinedione (TZD) drugs. We show here that PPAR gamma is expressed at significant levels in human primary and metastatic breast adenocarcinomas. Ligand activation of this receptor in cultured breast cancer cells causes extensive lipid accumulation, changes in breast epithelial gene expression associated with a more differentiated, less malignant state, and a reduction in growth rate and clonogenic capacity of the cells. Inhibition of MAP kinase, shown previously to be a powerful negative regulator of PPAR gamma, improves the TZD ligand sensitivity of nonresponsive cells. These data suggest that the PPAR gamma transcriptional pathway can induce terminal differentiation of malignant breast epithelial cells and thus may provide a novel, nontoxic therapy for human breast cancer.
我们之前已经证明，当被合成配体（如抗糖尿病噻唑烷二酮（TZD）药物）激活时，PPARγ会刺激脂肪细胞前体的终末分化。我们在此表明，PPARγ在人原发性和转移性乳腺腺癌中大量表达。在培养的乳腺癌细胞中该受体的配体激活会导致大量脂质积累、与更分化、恶性程度更低状态相关的乳腺上皮基因表达变化，以及细胞生长速率和克隆形成能力的降低。先前显示为PPARγ强大负调节因子的MAP激酶的抑制，可提高无反应细胞对TZD配体的敏感性。这些数据表明，PPARγ转录途径可诱导恶性乳腺上皮细胞的终末分化，因此可能为人类乳腺癌提供一种新的无毒治疗方法。
